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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2010-11-4
pubmed:abstractText
Acute lung injury (ALI) is a major cause of mortality in burn patients, even without direct inhalational injury. Identification of early mediators that instigate ALI after burn and of the molecular mechanisms by which they work are of high importance but remain poorly understood. We previously reported that an endogenous neuropeptide, substance P (SP), via binding neurokinin-1 receptor (NK1R), heightens remote ALI early after severe local burn. In this study, we examined the downstream signaling pathway following SP-NK1R coupling that leads to remote ALI after burn. A 30% total body surface area full-thickness burn was induced in male BALB/c wild-type (WT) mice, preprotachykinin-A (PPT-A) gene-deficient mice, which encode for SP, and PPT-A(-/-) mice challenged with exogenous SP. Local burn injury induced excessive SP-NK1R signaling, which activated ERK1/2 and NF-?B, leading to significant upregulation of cyclooxygenase (COX)-2, PGE metabolite, and remote ALI. Notably, lung COX-2 levels were abrogated in burn-injured WT mice by L703606, PD98059, and Bay 11-7082, which are specific NK1R, MEK-1, and NF-?B antagonists, respectively. Additionally, burn-injured PPT-A(-/-) mice showed suppressed lung COX-2 levels, whereas PPT-A(-/-) mice injected with SP showed augmented COX-2 levels postburn, and administration of PD98059 and Bay 11-7082 to burn-injured PPT-A(-/-) mice injected with SP abolished the COX-2 levels. Furthermore, treatment with parecoxib, a selective COX-2 inhibitor, attenuated proinflammatory cytokines, chemokines, and ALI in burn-injured WT mice and PPT-A(-/-) mice injected with SP. To our knowledge, we show for the first time that SP-NK1R signaling markedly elevates COX-2 activity via ERK1/2 and NF-?B, leading to remote ALI after burn.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1550-6606
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
185
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6265-76
pubmed:meshHeading
pubmed-meshheading:20926798-Acute Lung Injury, pubmed-meshheading:20926798-Animals, pubmed-meshheading:20926798-Blotting, Western, pubmed-meshheading:20926798-Burns, pubmed-meshheading:20926798-Chemokines, pubmed-meshheading:20926798-Cyclooxygenase 2, pubmed-meshheading:20926798-Cytokines, pubmed-meshheading:20926798-Disease Models, Animal, pubmed-meshheading:20926798-Enzyme Activation, pubmed-meshheading:20926798-Enzyme Inhibitors, pubmed-meshheading:20926798-Enzyme-Linked Immunosorbent Assay, pubmed-meshheading:20926798-Male, pubmed-meshheading:20926798-Mice, pubmed-meshheading:20926798-Mice, Inbred BALB C, pubmed-meshheading:20926798-Mice, Knockout, pubmed-meshheading:20926798-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:20926798-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:20926798-NF-kappa B, pubmed-meshheading:20926798-Prostaglandins E, pubmed-meshheading:20926798-Signal Transduction, pubmed-meshheading:20926798-Substance P, pubmed-meshheading:20926798-Up-Regulation
pubmed:year
2010
pubmed:articleTitle
Substance P upregulates cyclooxygenase-2 and prostaglandin E metabolite by activating ERK1/2 and NF-kappaB in a mouse model of burn-induced remote acute lung injury.
pubmed:affiliation
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't